Stimulators and/or activators of soluble guanylate cyclase (sgc) in combination with an inhibitor of neutral endopeptidase (nep inhibitor) and/or an angiotensin aii antagonist and the use thereof

ABSTRACT

The present invention relates to stimulators and activators of soluble guanylate cyclase in combination with an inhibitor of neutral endopeptidase and/or angiotensin AII antagonists and the use thereof for the treatment and/or prophylaxis of cardiovascular disorders, for example heart failure with preserved ejection fraction or heart failure with reduced ejection fraction, renal disorders, for example chronic kidney failure, urological disorders, lung disorders, disorders of the central nervous system, for regulation of cerebral perfusion, for example in the event of vascular cerebral states of dementia, for the treatment and/or prophylaxis of fibrotic disorders and other disease symptoms (e.g. end organ damage affecting the brain, kidney or heart).

The present invention relates to stimulators and/or activators ofsoluble guanylate cyclase in combination with an inhibitor of neutralendopeptidase and/or angiotensin AII antagonists and the use thereof forthe treatment and/or prophylaxis of cardiovascular disorders, forexample heart failure with preserved ejection fraction or heart failurewith reduced ejection fraction, renal disorders, for example chronickidney failure, urological disorders, lung disorders, disorders of thecentral nervous system, for regulation of cerebral perfusion, forexample in the event of vascular cerebral states of dementia, for thetreatment and/or prophylaxis of fibrotic disorders and other diseasesymptoms (e.g. end organ damage affecting the brain, kidney or heart).

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitrogenmonoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyze the biosynthesis of cGMP from guanosine triphosphate(GTP). The representatives of this family known to date can beclassified into two groups either by structural features or by the typeof ligands: the particulate guanylate cyclases which can be stimulatedby natriuretic peptides, and the soluble guanylate cyclases which can bestimulated by NO. The soluble guanylate cyclases consist of two subunitsand very probably contain one heme per heterodimer, which is part of theregulatory center. This is of central importance for the activationmechanism. NO is able to bind to the iron atom of heme and thus markedlyincrease the activity of the enzyme. Heme-free preparations cannot, bycontrast, be stimulated by NO. Carbon monoxide (CO) is also able to bindto the central iron atom of heme, but the stimulation by CO is much lessthan that by NO. The particulate membrane-bound guanylate cyclasesconsist of the cytosolic catalytic domain, a transmembrane region andthe extracellular ligand-binding domain. The binding of natriureticpeptides to the extracellular ligand-binding domain leads to theactivation of the catalytic domain and the biosynthesis of cGMP fromGTP. Neutral endopeptidase (neprilysin) inactivates natriuretic peptidesby proteolytic cleavage and consequently has an inhibiting effect on theparticulate guanylate cyclase.

By forming cGMP, and owing to the resulting regulation ofphosphodiesterases, ion channels and protein kinases, guanylate cyclaseplays an important role in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and platelet adhesion and in neuronal signaltransmission, and also in disorders which are based on a disruption ofthe aforementioned processes. Under pathophysiological conditions, theNO/cGMP system can be suppressed, which can lead, for example, tohypertension, platelet activation, increased cell proliferation,endothelial dysfunction, arteriosclerosis, angina pectoris, heartfailure, myocardial infarction, thromboses, stroke and sexualdysfunction.

Owing to the expected high efficiency and low level of side effects, apossible NO-independent treatment for such disorders by targeting theinfluence of the cGMP signal pathway in organisms is a promisingapproach.

Hitherto, for the therapeutic stimulation of the soluble guanylatecyclase, use has been made predominantly of compounds such as organicnitrates whose effect is based on direct release of NO. The latter isformed by bioconversion and activates soluble guanylate cyclase byattacking the central iron atom of heme. In addition to the sideeffects, the development of tolerance is one of the crucialdisadvantages of this mode of treatment.

By means of sGC activators and stimulators, the native as well as theheme-free form of soluble guanylate cyclase are directly activated orstimulated.

Using sGC activators, it is also possible to directly stimulate oxidizedforms of soluble guanylate cyclase, and ultimately the heme-free form ofsGC, independently of NO. This oxidized/heme-free form may accumulate inrelatively high concentrations in tissue exposed to oxidative stress, sothat, by using sGC activators, there should also be a targeted treatmentof tissue under oxidative stress.

LCZ696 is an ARM (angiotensin receptor neprilysin inhibitor) andtherefore a dual active ingredient consisting of the angiotensin AIIantagonist valsartan and the neprilysin inhibitor sacubitril. By meansof neprilysin inhibition, reduced degradation of natriuretic peptides isachieved. These have in particular a diuretic and natriuretic effect dueto their vasodilatory effects on preglomerular vessels. In addition,they can also inhibit sodium resorption in proximal tubule sections.

The combination of angiotensin receptor blockade and neprilysininhibition by LCZ696 (a combination of the angiotensin receptorantagonist valsartan and the NEP inhibitor sacubitril) was recentlyinvestigated in clinical trials (phase III) in patients with heartfailure and resulted in a reduction in the risk of death andhospitalization (McMurray et al 2014 NEJM). In addition to the desiredincrease in ANP and cGMP, a compensatory increase in renin andangiotensin was measured on LCZ696 administration both in healthysubjects and in hypertensive patients (Gu J. et al J Clin Pharmacol.2010 April; 50(4):401-14).

A disadvantage of the administration of LCZ696 for reducing bloodpressure is that compensatory effects of the heart rate, such as, forexample, a reflex tachycardia with accompanying blood pressure reductioncan be observed.

Accordingly, the object of the present invention is to providecombinations of pharmaceutical active ingredients for the treatment ofcardiovascular disorders which reduce the mean arterial blood pressureand have as little as possible or no effect on hemodynamic parameterssuch as heart rate. This is intended to overcome the disadvantagesdescribed above, the compensatory effects of the heart rate, which areassociated with a reduction in blood pressure.

In order to achieve this object, sGC stimulators and/or sGC activatorsin combination with neprilysin inhibitors and/or angiotensin AIIantagonists were investigated under acute and, in particular, underchronic use, with the assumption that under experimental conditionspositive effects on blood pressure and heart rate can be shown which arecaused by the resulting plasma and tissue cGMP levels. Theseexperimental conditions consist of healthy animals or also animals withhypertension (e.g. spontaneously hypertensive rats). In this case, theexperiments are conducted with sGC stimulators and/or activators“head-to-head” against the sole combination of neprilysin inhibitors andangiotensin AII antagonists, such as, for example, LCZ696.

These experiments are intended to determine whether the enhancement ofcGMP by stimulating the soluble guanylate cyclase with sGC stimulatorsand/or activators in combination with sacubitril (activation of theparticulate, membrane-dependent guanylate cyclase by inhibition ofneprilysin) and/or an angiotensin AII antagonist has an advantageouseffect on, for example, hemodynamic parameters such as heart rate andmean arterial blood pressure.

The solution to the object stated above and the subject matter of thepresent invention are the following combinations of sGC stimulatorsand/or sGC activators with neprilysin inhibitors and/or angiotensin AIIantagonists.

The combination of stimulators and/or activators of soluble guanylatecyclase with a neprilysin inhibitor and/or an angiotensin AII antagonistleads to vessel relaxation and/or controllable reduction in bloodpressure. The combination is therefore suitable for the treatment and/orprophylaxis of diseases, preferably cardiovascular disorders,particularly for the treatment and/or prophylaxis of heart failure withpreserved ejection fraction or heart failure with reduced ejectionfraction, renal disorders, lung disorders, and for the treatment and/orfibrotic disorders in humans and animals.

Angiotensin AII antagonists of the combinations according to the presentinvention administered are, by way of example and preferably, valsartan,losartan, candesartan, telmisartan, irbesartan, olmesartan, eprosartanor azilsartan and preferably valsartan.

Valsartan is the angiotensin AII antagonist(S)—N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amineof the formula (30)

or a salt, solvate or solvate of the salts thereof and has beendescribed in EP 0 443 983 A and U.S. Pat. No. 5,399,578 A.

The NEP inhibitor of the combinations according to the present inventionisN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid of the formula (31)

or an ester of the acid or in each case a salt, solvate or solvate ofthe salts of the acid or ester. Acid and ester of the NEP inhibitor ofthe combinations according to the present invention are described in EP0 555 175 A1.

A preferred form ofN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid is in the form of the ethyl ester, ethylN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoate.

With respect to ethylN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoate,preferred salts include the sodium salt, the triethanolamine salt andthe tris(hydroxymethyl)aminomethane salt.

In the combinations according to the invention, valsartan and the NEPinhibitor may be present in each case individually or as tri sodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.

The trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate complex, also known as LCZ696, is described in moredetail in EP 1 948 158 A1.

sGC stimulators and activators in the context of the combinationsaccording to the present invention are the compounds disclosed in thefollowing published specifications: WO03/097063, WO03/09545,WO04/009589, WO03/004503, WO02/070462, WO2007/045366, WO2007/045369,WO2007/045370, WO2007/045433, WO2007/045367, WO2007/124854,WO2007/128454, WO2008/031513, WO2008/061657, WO2008/119457,WO2008/119458, WO2009/127338, WO2010/079120, WO2010/102717,WO2011/051165, WO2011/147809, WO2011/141409, WO2014/012935,WO2012/059549, WO2012/004259, WO2012/004258, WO2012/059548,WO2012/028647, WO2012/152630, WO2012/076466, WO2014/068099,WO2014/068104, WO2012/143510, WO2012/139888, WO2012/152629,WO2013/004785, WO2013/104598, WO2013/104597, WO2013/030288,WO2013/104703, WO2013/131923, WO2013/174736, WO2014/012934,WO2014/068095, WO2014/195333, WO2014/128109, WO2014/131760,WO2014/131741, WO2015/018808, WO2015/004105, WO2015/018814, WO98/16223,WO98/16507, WO98/23619, WO00/06569, WO01/19776, WO01/19780, WO01/19778,WO02/042299, WO02/092596, WO02/042300, WO02/042301, WO02/036120,WO02/042302, WO02/070459, WO02/070460, WO02/070461, WO02/070510,WO2012/165399, WO2014/084312, WO2011/115804, WO2012/003405,WO2012/064559, WO2014/047111, WO2014/047325, WO2011/149921,WO2010/065275, WO2011/119518, WO2015/08885, WO2015/08886, WO2014/144100.

Preferred sGC stimulators and activators in the context of thecombinations according to the present invention are

2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), disclosed as example 16 inWO 00/06569,

-   -   2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-(4-pyridinyl)-4-pyrimidineamine        (2), disclosed as example 1 in WO 02/42301,    -   methyl        4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate        (3), disclosed as example 8 in WO 03/095451,    -   methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo        [3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate (4), disclosed as        example 5 in WO 03/095451,    -   4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)carboxylic        acid (5), disclosed as example 8a in WO 01/019780,    -   methyl        {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-5-yl}carbamate        (6), methyl        {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-5-yl}methylcarbamate        (7), methyl        {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}(2,2,2-trifluoroethyl)carbamate        (8), disclosed in WO 2011/147809,    -   5-chloro-2-(5-chlorothiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide        as sodium salt (9), disclosed in WO00/02851,    -   2-(4-chlorophenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide        (10), disclosed in WO00/02851,    -   1-{6-[5-chloro-2-({4-trans-4-}trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic        acid (11), disclosed in WO 2009/032249,    -   1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)phenyl)pyridin-2-yl]-5-trifluoromethylpyrazole-4-carboxylic        acid (12), disclosed in WO 2009/071504,    -   1[6-(3,4-dichlorophenyl)-2-pyridinyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic        acid (13), disclosed in WO 2009/068652,    -   1-({2-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-4-yl}methyl)-1H-pyrazole-4-carboxylic        acid (14),        4-({2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)benzoic        acid (15) and        1-({2-[2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-4-yl}methyl)-1H-pyrazole-4-carboxylic        acid (16) disclosed in WO 2009/123316,    -   4-amino-2-[5-chloro-3(3,3,3-trifluoropropyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (17),        4-amino-2[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (18),        4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)1H-thieno[3,4-c]pyrazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (19),        4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[2,3-d]pyrazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (20),        4-amino-5,5-dimethyl-2-[7-(2,3,6-trifluorobenzypimidazo[1,5-b]pyridazin-5-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (21),        4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (22),        4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (23),        4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)6-fluoroimidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3        -d]pyrimidin-6-one (24),        4-amino-5,5-dimethyl-2-[3-(2,4,6-trifluorobenzyl)imidazo[1,5        -a]pyridin-1-yl]]-5,7-dihydro-6H-pyrrolo [2,3-d]pyrimidin-6-one        (25), 4-amino-2-[3-(2-cyclopentylethypimidazo[1,5        -a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (26), disclosed in WO 2010/065275,    -   3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo        [3,4-b]pyridine (27), known as BAY 41-2272 disclosed as example        1 in WO 00/06568,    -   2-{5-fluoro-1-[3-fluoropyridin-2-yl)methyl]-1H-pyrazolo        [3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one        (28), disclosed as example 1 in WO 2014/131760,    -   3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic        acid (29) disclosed as example 22 in WO 2012/139888,    -   5-{[2-(4-carboxypheny)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic        acid formula (32) and        5-{(4-carboxybutyl)[2-(2{-[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic        acid of the formula (33) are disclosed as examples in WO        2014/012934,    -   ent-N-[(2S)-amino-2-methylbutyl]-8-[(2,6-difluorobenzypoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide        (enantiomer A) of the formula (34),        ent-N-(2-amino-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide        (enantiomer B) of the formula (35),        ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide        (enantiomer B) of the formula (36),        ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzypoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide        (enantiomer B) of the formula (37),        ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6-difluorobenzypoxy]-2,6-dimethylimidazo        [1,2-a]pyridine-3-carboxamide (enantiomer A) of the formula        (38),        ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide        (enantiomer B) of the formula (39),        ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide        (enantiomer B) of the formula (40),        ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide        (enantiomer A) of the formula (41),        rac-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzypoxy]-2,6-dimethylimidazo        [1,2-a]pyridine-3-carboxamide formate of the formula (42),        ent-N-(2-amino-3-fluoro-2-methylpropyl)-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxamide        (enantiomer A) of the formula (43),        ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide        (enantiomer B) of the formula (44),        ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-6-(difluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide        (enantiomer A) of the formula (45),        ent-N-(2-amino-3-fluoro-2-methylpropyl)-8-[(2,6-difluorobenzypoxy]-6-(fluoromethyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide        of the formula (46) are disclosed as examples in WO 2014/068099.

Compounds of the formulae (1), (2), (3), (4), (6)-(8), (17)-(27) and(34)-(46) are known as sGC stimulators.

Compounds of the formulae (5) and (9)-(16), (29), (32) and (33) areknown as sGC activators.

In the context of the combinations according to the invention,preference is given to sGC stimulators of the formulae (1), (2), (3),(4), (6)-(8) and (17)-(27) and activators of the formulae (5) and(9)-(16) and (29).

In the context of the combinations according to the invention, preferredsGC stimulators are compounds of the formulae (1), (2), (3), (4), (6),(7), (27) and (28).

In the context of the combinations according to the invention,particularly preferred are the sGC stimulators of the formulae (3), (4),(6), (7) and (28).

In the context of the combinations according to the invention,particularly preferred are the sGC stimulators of the formulae (3) and(6).

In the context of the combinations according to the invention,particularly preferred is the sGC stimulator of the formula (6).

Particularly preferred in the context of the combinations according tothe invention is the sGC activator of the formula (29).

The combinations according to the invention allow an effective treatmentof cardiovascular diseases by reducing the mean arterial blood pressureand, as far as possible, no or little effects on the hemodynamicparameters, such as the heart rate, occur. Therefore, the disadvantagesdescribed above of the therapy forms known in the prior art, such as,for example, compensatory effects of the heart rate with accompanyingblood pressure reduction, could be overcome.

Moreover, the combinations according to the invention show anunforeseeable, valuable pharmacological and pharmacokinetic spectrum ofactivity.

The combinations according to the invention are suitable for theprophylaxis and/or treatment of diseases due to their vessel-relaxingeffect (vasorelaxation) and inhibition of platelet aggregation and leadto a decrease in blood pressure and to a rise in the coronary bloodflow. These effects are mediated by stimulation of the soluble and/orparticulate guanylate cyclase and/or blockade of the angiotensinreceptor. In addition, the combinations according to the inventionenhance the action of substances which increase the cGMP level, forexample EDRF (endothelium-derived relaxing factor), NO donors,protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

The present invention further relates to the use of sGC activatorsand/or sGC stimulators in combination with neprilysin inhibitors and/orangiotensin AII antagonists for the treatment of cardiovasculardisorders, for example heart failure with preserved ejection fraction orheart failure with reduced ejection fraction, renal disorders, forexample chronic kidney failure, urological disorders, lung disorders,disorders of the central nervous system, for regulation of cerebralperfusion, for example in the event of vascular cerebral states ofdementia, for the treatment and/or prophylaxis of fibrotic disorders andother disease symptoms (e.g. end organ damage affecting the brain,kidney or heart).

The present invention further relates to sGC activators and/or sGCstimulators in combination with angiotensin AII antagonists and also theuse thereof for the treatment of cardiovascular disorders, for exampleheart failure with preserved ejection fraction or heart failure withreduced ejection fraction, renal disorders, for example chronic kidneyfailure, urological disorders, lung disorders, disorders of the centralnervous system, for regulation of cerebral perfusion, for example in theevent of vascular cerebral states of dementia, for the treatment and/orprophylaxis of fibrotic disorders and other disease symptoms (e.g. endorgan damage affecting the brain, kidney or heart).

By way of preference, the invention relates to administration of sGCstimulators and/or activators in combination with a neprilysin inhibitorsuch as, for example and with preference sacubitril and/or anangiotensin AII antagonist such as, for example and with preferencevalsartan, losartan, candesartan, telmisartan, irbesartan, olmesartan,eprosartan or azilsartan.

By way of preference, the present invention relates to combinationscomprising an sGC stimulator and/or sGC activator,N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof and/or valsartan and in each case the salts,solvates and solvates of the salts of an sGC stimulator and/or sGCactivator,N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof and/or valsartan.

The present invention further relates to combinations comprising an sGCstimulator and/or sGC activator and LCZ696 and also in each case thesalts, solvates and solvates of the salts thereof.

The present invention particularly preferably relates to combinationscomprising an sGC stimulator, sacubitril and/or an angiotensin AIIantagonist and also in each case the salts, solvates and solvates of thesalts thereof.

The present invention furthermore particularly preferably relates tocombinations comprising an sGC stimulator, sacubitril and/or valsartanand also in each case the salts, solvates and solvates of the saltsthereof.

The present invention furthermore particularly preferably relates tocombinations comprising an sGC stimulator and LCZ696 and also in eachcase the salts, solvates and solvates of the salts thereof.

The present invention furthermore particularly preferably relates tocombinations comprising the compound of the formula (6),N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof and/or valsartan, and in each case the salts,solvates and solvates of the salts of the compound of the formula (6)andN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof and/or valsartan.

The present invention furthermore particularly preferably relates tocombinations comprising the compound of the formula (6) and LCZ696 andalso in each case the salts, solvates and solvates of the salts thereof.

The present invention further relates to combinations comprising an sGCstimulator and/or sGC activator and valsartan, and also in each case thesalts, solvates and solvates of the salts of an sGC stimulator and/orsGC activator and valsartan.

The present invention further relates to combinations comprising thecompound of the formula (6) and valsartan, and also in each case thesalts, solvates and solvates of the salts of the compound of the formula(6) and valsartan.

The components to be combined may be present as salts. Preferred saltsin the context of the present invention are physiologically acceptablesalts of the compounds to be combined. Also included are salts which arenot themselves suitable for pharmaceutical applications but can be used,for example, for isolation or purification of the compounds to becombined.

The present invention further relates to combinations in which the molarratio of the compound of the formula (6) to valsartan to N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acidor an ester thereof is 0.01-1:1:1.

The present invention further relates to combinations in which the molarratio of the compound of the formula (6) to trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(5)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate is 0.01-1:1.

The present invention further relates to combinations in which the molarratio of the compound of the formula (6) to N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid or an esterthereof is 0.01-1:1.

The present invention further relates to combinations in which the molarratio of the compound of the formula (6) to valsartan is 0.01-1:1.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein thecompound of the formula (6) is administered once daily and valsartan andethyl N-(3 -carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoate or N-(3 -carboxy-1-oxopropyl)-(4 S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid or an ester thereofare administered twice daily.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein1.25-20 mg of the compound of the formula (6), 20-200 mg of valsartanand 20-200 mg ofN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof are administered.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein1.25-20 mg of the compound of the formula (6) and 20-200 mg ofN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof are administered.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein1.25-20 mg of the compound of the formula (6) and 20-200 mg of valsartanare administered.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein thecompound of the formula (6) is administered once daily and trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate is administered twice daily.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein1.25-20 mg of the compound of the formula (6) and 40-400 mg of trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate are administered.

The present invention further relates to combinations according to theinvention, wherein the molar ratio of the compound of the formula (6) tovalsartan toN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof is 0.001-1:1:3, 0.001-1:3:1, 0.001-1:1:2,0.001-1:2:1 or 0.001-1:1:1, preferably 0.005-0.75:1:3, 0.005-0.75:3:1,0.005-0.75:1:2, 0.005-0.75:2:1 or 0.005-0.75:1:1 and most preferably0.01-0.5:1:1.

The present invention further relates to combinations according to theinvention, wherein the molar ratio of the compound of the formula (6) totrisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″ -(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate is 0.001-1:1, preferably 0.005-0.75:1 and mostpreferably 0.01-0.5:1.

The present invention further relates to combinations comprising thecompound of the formula (29),N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof and/or valsartan, and also in each case thesalts, solvates and solvates of the salts of the compound of the formula(29),N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof and/or valsartan.

The present invention further relates to combinations comprising thecompound of the formula (29) and trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrateand also in each case the salts, solvates and solvates of the saltsthereof.

The present invention further relates to combinations comprising thecompound of the formula (29) and valsartan, and also in each case thesalts, solvates and solvates of the salts of the compound of the formula(29) and valsartan.

The present invention further relates to combinations in which the molarratio of the compound of the formula (29) to valsartan toN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof is 0.02-1:1:1.

The present invention further relates to combinations in which the molarratio of the compound of the formula (29) to trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate is 0.02-1:1.

The present invention further relates to combinations in which the molarratio of the compound of the formula (29) to N-(3-carboxy-1-oxopropyl)-(4 S)-(p -phenylphenylmethyl)-4-amino-2R-methylbutanoic acid or the esters thereof is 0.02-1:1.

The present invention further relates to combinations in which the molarratio of the compound of the formula (29) to valsartan is 0.02-1:1.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein thecompound of the formula (29) is administered once daily and valsartanand ethylN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoateor N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmthyl)-4-amino-2R-methylbutanoic acid are administered twice daily.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein2.5-20 mg of the compound of the formula (29), 20-200 mg of valsartanand 20-200 mg ofN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof are administered.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein2.5-20 mg of the compound of the formula (29) and 20-400 mg ofN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof are administered.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein2.5-20 mg of the compound of the formula (29), 20-400 mg of valsartan orthe esters thereof are administered.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein thecompound of the formula (29) is administered once daily and trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate is administered twice daily.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases, wherein2.5-20 mg of the compound of the formula (29) and 40-400 mg of trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5 -ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate are administered.

The present invention further relates to combinations according to theinvention, wherein the molar ratio of the compound of the formula (29)to valsartan toN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof is 0.001-1:1:3, 0.001-1:3:1, 0.001-1:1:2,0.001-1:2:1 or 0.001-1:1:1, preferably 0.005-0.75:1:3, 0.005-0.75:3:1,0.005-0.75:1:2, 0.005-0.75:2:1 or 0.005-0.75:1:1 and most preferably0.02-0.5:1:1.

The present invention further relates to combinations according to theinvention, wherein the molar ratio of the compound of the formula (29)to trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate is 0.001-1:1, preferably 0.005-0.75:1 and mostpreferably 0.01-0.5:1.

The present invention further relates to combinations according to theinvention for the treatment and/or prophylaxis of diseases.

The present invention further relates to combinations according to theinvention for use in a method for the treatment and/or prophylaxis ofcardiovascular disorders, renal disorders, lung disorders, and also forthe treatment and/or prophylaxis of fibrotic disorders.

The present invention further relates to a medicament comprising atleast one combination according to the invention in combination with aninert, non-toxic, pharmaceutically suitable excipient.

The present invention further relates to a medicament comprising atleast one combination according to the invention in combination with oneor more further active ingredients selected from the group consisting ofACE inhibitors, renin inhibitors, beta blockers, acetylsalicylic acid,diuretics, calcium antagonists, statins, digitalis (digoxin)derivatives, calcium sensitizers, nitrates and antithrombotics.

The present invention further relates to a medicament comprising atleast one combination according to the invention for the treatmentand/or prophylaxis of cardiovascular disorders, renal disorders, lungdisorders, and also for the treatment and/or prophylaxis of fibroticdisorders.

The present invention further relates to a method for the treatmentand/or prophylaxis of cardiovascular disorders, renal disorders, lungdisorders, and also for the treatment and/or prophylaxis of fibroticdisorders, in humans and animals using at least one combinationaccording to the invention.

The invention also relates to the combination of separate pharmaceuticalcompositions in kit form. This is a kit comprising two or three separateunits: a pharmaceutical composition of an sGC stimulator and/or sGCactivator, a pharmaceutical NEP inhibitor composition and/or apharmaceutical valsartan composition.

The invention also relates to a preferred kit form comprising two units:a pharmaceutical composition comprising an sGC stimulator and/or sGCactivator and a pharmaceutical composition comprising an NEP inhibitorand/or valsartan.

The invention also relates to a preferred kit form comprising two units:a pharmaceutical composition comprising an sGC stimulator and/or sGCactivator and a pharmaceutical composition comprising LCZ696.

The invention also relates to a preferred kit form comprising two units:a pharmaceutical composition comprising the compound of the formula (6)and a pharmaceutical composition comprising LCZ696.

The invention also relates to a preferred kit form comprising two units:a pharmaceutical composition comprising the compound of the formula (29)and a pharmaceutical composition comprising LCZ696.

The kit is particularly advantageous if the separate components have tobe administered in different dose forms or in different dose intervals.

The present invention further relates to a kit comprising apharmaceutical composition comprising an sGC stimulator and/or sGCactivator and a pharmaceutical composition comprising an angiotensin AIIantagonist andN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof.

The present invention further relates to a kit comprising apharmaceutical composition comprising an sGC stimulator and/or sGCactivator and a pharmaceutical composition comprising valsartan andN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof.

The present invention further relates to a kit comprising apharmaceutical composition comprising an sGC stimulator and/or sGCactivator and a pharmaceutical composition comprising trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.

The present invention further relates to a kit comprising apharmaceutical composition comprising the compound of the formula (6)and a pharmaceutical composition comprising valsartan andN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof.

The present invention further relates to a kit comprising apharmaceutical composition comprising the compound of the formula (6)and a pharmaceutical composition comprising trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate.

The present invention further relates to a kit comprising apharmaceutical composition comprising the compound of the formula (29)and a pharmaceutical composition comprising valsartan andN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or the esters thereof.

The present invention further relates to a kit comprising apharmaceutical composition comprising the compound of the formula (29)and a pharmaceutical composition comprising trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.

Accordingly, the combinations according to the invention can be used inmedicaments for the treatment and/or prophylaxis of cardiovasculardisorders such as, for example, elevated blood pressure (hypertension),resistant hypertension, acute and chronic heart failure, heart failurewith preserved ejection fraction (HFpEF) or heart failure with reducedejection fraction (HFrEF), coronary heart disease, stable and unstableangina pectoris, peripheral and cardiac vascular disorders, arrhythmias,atrial and ventricular arrhythmias and impaired conduction such as, forexample, atrioventricular blocks degrees I-III (AB block I-III),supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter,ventricular fibrillation, ventricular flutter, ventriculartachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricularextrasystoles, AV junctional extrasystoles, sick sinus syndrome,syncopes, AV-nodal re-entry tachycardia, Wolff-Parkinson-White syndrome,of acute coronary syndrome (ACS), autoimmune cardiac disorders(pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies),shock such as cardiogenic shock, septic shock and anaphylactic shock,aneurysms, boxer cardiomyopathy (premature ventricular contraction(PVC)), for the treatment and/or prophylaxis of thromboembolic disordersand ischemias such as myocardial ischemia, myocardial infarction,stroke, cardiac hypertrophy, transient and ischemic attacks,preeclampsia, inflammatory cardiovascular disorders, spasms of thecoronary arteries and peripheral arteries, edema formation such as, forexample, pulmonary edema, cerebral edema, renal edema or edema caused byheart failure, peripheral circulatory disturbances, reperfusion damage,arterial and venous thromboses, microalbuminuria, myocardialinsufficiency, endothelial dysfunction, to prevent restenoses, forexample after thrombolysis therapies, percutaneous transluminalangioplasties (PTA), transluminal coronary angioplasties (PTCA), hearttransplants and bypass operations, and also micro- and macrovasculardamage (vasculitis), increased levels of fibrinogen and of low-densitylipoprotein (LDL) and increased concentrations of plasminogen activatorinhibitor 1 (PAI-1), and also for the treatment and/or prophylaxis ofmale erectile dysfunction and female sexual dysfunction.

In the context of the present invention, the term “heart failure”encompasses both acute and chronic manifestations of heart failure, andalso more specific or related types of disease, such as acutedecompensated heart failure, right heart failure, left heart failure,global failure, ischamic cardiomyopathy, dilated cardiomyopathy,hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heartdefects, heart failure associated with heart valve defects, mitral valvestenosis, mitral valve insufficiency, aortic valve stenosis, aorticvalve insufficiency, tricuspid valve stenosis, tricuspid valveinsufficiency, pulmonary valve stenosis, pulmonary valve insufficiency,combined heart valve defects, myocardial inflammation (myocarditis),chronic myocarditis, acute myocarditis, viral myocarditis, diabeticheart failure, alcoholic cardiomyopathy, cardiac storage disorders,diastolic heart failure and systolic heart failure and acute phases ofworsening of existing chronic heart failure (worsening heart failure).

In addition, the combinations according to the invention can also beused for the treatment and/or prophylaxis of arteriosclerosis, impairedlipid metabolism, hypolipoproteinemias, dyslipidemias,hypertriglyceridemias, hyperlipidemias, hypercholesterolemias,abetelipoproteinemia, sitosterolemia, xanthomatosis, Tangier disease,adiposity, obesity and of combined hyperlipidemias and metabolicsyndrome.

The combinations according to the invention can also be used for thetreatment and/or prophylaxis of primary and secondary Raynaud'sphenomenon, microcirculation impairments, claudication, peripheral andautonomic neuropathies, diabetic microangiopathies, diabeticretinopathy, diabetic ulcers on the extremities, gangrene, CRESTsyndrome, erythematosis, onychomycosis, rheumatic disorders and forpromoting wound healing. The combinations according to the invention arealso suitable for the treatment of muscular dystrophy, such asBecker-Kiener muscular dystrophy (BMD) and Duchenne muscular dystrophy(DMD).

The combinations according to the invention are furthermore suitable forthe treatment and/or prophylaxis of urological disorders such as, forexample, benign prostate syndrome (BPS), benign prostate hyperplasia(BPH), benign prostate enlargement (BPE), bladder outlet obstruction(BOO), lower urinary tract syndromes (LUTS, including Feline UrologicalSyndrome (FUS)), disorders of the urogenital system including neurogenicover-active bladder (OAB) and (IC), incontinence (UI) such as, forexample, mixed urinary incontinence, urge urinary incontinence, stressurinary incontinence or overflow urinary incontinence (MUI, UUI, SUI,OUI), pelvic pain, benign and malignant disorders of the organs of themale and female urogenital system.

The combinations according to the invention are also suitable for thetreatment and/or prophylaxis of kidney disorders, in particular of acuteand chronic renal insufficiency and acute and chronic kidney failure. Inthe context of the present invention, the term “renal insufficiency”encompasses both acute and chronic manifestations of renalinsufficiency, and also underlying or related renal disorders such asrenal hypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathies, glomerulonephritis, acute glomerulonephritis,glomerulosclerosis, tubulointerstitial diseases, nephropathic disorderssuch as primary and congenital kidney disease, nephritis, immunologicalkidney disorders such as kidney transplant rejection andimmunocomplex-induced kidney disorders, nephropathy induced by toxicsubstances, nephropathy induced by contrast agents, diabetic andnon-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis,hypertensive nephrosclerosis and nephrotic syndrome which can becharacterized diagnostically, for example by abnormally reducedcreatinine and/or water excretion, abnormally elevated bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes, for example glutamyl synthetase, alteredurine osmolarity or urine volume, elevated microalbuminuria,macroalbuminuria, lesions on glomerulae and arterioles, tubulardilatation, hyperphosphatemia and/or need for dialysis. The presentinvention also encompasses the use of the combinations according to theinvention for the treatment and/or prophylaxis of sequelae of renalinsufficiency, for example pulmonary edema, heart failure, uremia,anemia, electrolyte disorders (for example hyperkalemia, hyponatremia)and disorders in bone and carbohydrate metabolism.

In addition, the combinations according to the invention are alsosuitable for the treatment and/or prophylaxis of asthmatic disorders,lung disorders such as pulmonary arterial hypertension (PAH) and otherforms of pulmonary hypertension (PH) including left-heart disease-,HIV-, sickle cell anemia-, thromboembolism- (CTEPH), sarcoidosis-, COPD-or pulmonary fibrosis-associated pulmonary hypertension,chronic-obstructive pulmonary disease (COPD), acute respiratory distresssyndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency(AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonaryemphysema induced by cigarette smoke) and cystic fibrosis (CF). Inaddition, the combinations mentioned according to the invention may beused as bronchodilators.

The combinations described in the present invention are alsocombinations for the treatment and/or prophylaxis of central nervoussystem disorders characterized by disturbances of the NO/cGMP system.They are suitable in particular for improving perception, concentration,learning or memory after cognitive impairments like those occurring inparticular in association with situations/diseases/syndromes such asmild cognitive impairment, age-associated learning and memoryimpairments, age-associated memory losses, vascular dementia,craniocerebral trauma, stroke, dementia occurring after strokes(post-stroke dementia), post-traumatic craniocerebral trauma, generalconcentration impairments, concentration impairments in children withlearning and memory problems, Alzheimer's disease, Lewy body dementia,dementia with degeneration of the frontal lobes including Pick'ssyndrome, Parkinson's disease, progressive nuclear palsy, dementia withcorticobasal degeneration, amyolateral sclerosis (ALS), Huntington'sdisease, demyelinization, multiple sclerosis, thalamic degeneration,Creutzfeldt-Jakob dementia, HIV dementia, schizophrenia with dementia orKorsakoff s psychosis. They are also suitable for the treatment and/orprophylaxis of central nervous system disorders such as states ofanxiety, tension and depression, CNS-related sexual dysfunctions andsleep disturbances, and for controlling pathological disturbances of theintake of food, stimulants and addictive substances.

In addition, the combinations according to the invention are alsosuitable for the regulation of cerebral perfusion and for example areeffective agents for controlling vascular cerebral dementia andmigraine. They are also suitable for the prophylaxis and control ofsequelae of cerebral infarct (Apoplexia cerebri) such as stroke,cerebral ischemias and skull-brain trauma. The combinations according tothe invention can likewise be used for controlling states of pain andtinnitus.

In addition, the combinations according to the invention haveanti-inflammatory action and can therefore be used as anti-inflammatoryagents for the treatment and/or prophylaxis of sepsis (SIRS), multipleorgan failure (MODS, MOF), inflammatory disorders of the kidney, chronicintestinal inflammations (IBD, Crohn's disease, UC), pancreatitis,peritonitis, rheumatoid disorders, inflammatory skin disorders andinflammatory eye disorders.

Furthermore, the combinations according to the invention may also beused for the treatment and/or prophylaxis of autoimmune diseases.

The combinations according to the invention may also be suitable for thetreatment and/or prophylaxis of fibrotic disorders of the internalorgans, for example the lung, the heart, the kidney, the skin, the bonemarrow and in particular the liver, and also dermatological fibroses andfibrotic eye disorders. In the context of the present inventions, theterm “fibrotic disorders” includes in particular the following terms:hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis,endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitialrenal fibrosis, fibrotic damage resulting from diabetes, bone marrowfibrosis and similar fibrotic disorders, systemic sclerosis,scleroderma, digital ulcerations, morphea, keloids, hypertrophicscarring (also following surgical procedures), nevi, diabeticretinopathy, proliferative vitroretinopathy and disorders of theconnective tissue (for example sarcoidosis).

The combinations according to the invention are also suitable forcontrolling postoperative scarring, for example as a result of glaucomaoperations.

The combinations according to the invention may also be usedcosmetically for ageing and keratinizing skin.

Moreover, the combinations according to the invention are suitable forthe treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis,bone formation disorders, glaucoma and gastroparesis.

The combinations according to the invention can be used alone or, ifrequired, in combination with other active ingredients.. The presentinvention further provides medicaments comprising at least one of thecombinations according to the invention and one or more further activeingredients, especially for the treatment and/or prophylaxis of theaforementioned disorders. Preferred examples of suitable combinationactive ingredients include:

-   -   hypotensive active ingredients, by way of example and with        preference from the group of angiotensin AII antagonists, ACE        inhibitors, calcium antagonists, endothelin antagonists, renin        inhibitors, alpha receptor blockers, beta receptor blockers,        mineralocorticoid receptor antagonists and also the diuretics;    -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds which inhibit the breakdown of cyclic guanosine        monophosphate (cGMP), for example inhibitors of        phosphodiesterases (PDE) 1, 2, 5 and/or 9, especially PDE 5        inhibitors such as sildenafil, vardenafil and tadalafil;    -   antithrombotics, by way of example and with preference from the        group of the platelet aggregation inhibitors, the anticoagulants        or the profibrinolytic substances;    -   active compounds which alter lipid metabolism, by way of example        and with preference from the group of thyroid receptor agonists,        cholesterol synthesis inhibitors, preferred examples being        HMG-CoA reductase inhibitors or squalene synthesis inhibitors,        of ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha,        PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption        inhibitors, lipase inhibitors, polymeric bile acid adsorbents,        bile acid reabsorption inhibitors and lipoprotein(a)        antagonists.

Antithrombotic agents are preferably understood to mean compounds fromthe group of the platelet aggregation inhibitors, the anticoagulants orthe profibrinolytic substances.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a plateletaggregation inhibitor, by way of example and with preference aspirin,clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a thrombininhibitor, by way of example and with preference ximelagatran,dabigatran, melagatran, bivalirudin or clexane.

In a preferred embodiment, the combinations according to the inventionare administered in combination with a GPIIb/IIIa antagonist, by way ofexample and with preference tirofiban or abciximab.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a factor Xainhibitor, by way of example and with preference rivaroxaban, DU-176b,apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux,PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with heparin or with alow molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a vitamin Kantagonist, by way of example and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from thegroup of the calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha receptorblockers, beta receptor blockers, mineralocorticoid receptorantagonists, and the diuretics.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a calciumantagonist, by way of example and with preference nifedipine,amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with an alpha-1receptor blocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a beta receptorblocker, by way of example and with preference propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with an angiotensin AIIantagonist, by way of example and with preference losartan, candesartan,valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with an ACE inhibitor,by way of example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with an endothelinantagonist, by way of example and with preference bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a renin inhibitor,by way of example and with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with amineralocorticoid receptor antagonist, by way of example and withpreference spironolactone or eplerenone.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a loop diuretic,for example furosemide, torasemide, bumetanide and piretanide, withpotassium-sparing diuretics, for example amiloride and triamterene, withaldosterone antagonists, for example spironolactone, potassiumcanrenoate and eplerenone, and also thiazide diuretics, for examplehydrochlorothiazide, chlorthalidone, xipamide and indapamide.

Lipid metabolism modifiers are preferably understood to mean compoundsfrom the group of the CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbers, bile acidreabsorption inhibitors, lipase inhibitors and the lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a CETP inhibitor,by way of example and with preference dalcetrapib, BAY 60-5521,anacetrapib or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a thyroid receptoragonist, by way of example and with preference D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with an HMG-CoAreductase inhibitor from the class of statins, by way of example andwith preference lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a squalenesynthesis inhibitor, by way of example and with preference BMS-188494 orTAK-475.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with an ACAT inhibitor,by way of example and with preference avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with an MTP inhibitor,by way of example and with preference implitapide, BMS-201038, R-103757or JTT-130.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a PPAR-gammaagonist, by way of example and with preference pioglitazone orrosiglitazone.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a PPAR-deltaagonist, by way of example and with preference GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a cholesterolabsorption inhibitor, by way of example and with preference ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a lipaseinhibitor, by way of example and with preference orlistat.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a polymeric bileacid adsorber, by way of example and with preference cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a bile acidreabsorption inhibitor, by way of example and with preference ASBT(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the combinations accordingto the invention are administered in combination with a lipoprotein(a)antagonist, by way of example and with preference gemcabene calcium(CI-1027) or nicotinic acid.

In the combinations according to the invention, the components can actsystemically and/or locally. For this purpose, they can be administeredin a suitable manner, for example by the oral, parenteral, pulmonal,nasal, sublingual, lingual, buccal, rectal, dermal, transdermal,conjunctival or otic route, or as an implant or stent.

The combinations according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichfunction according to the prior art and release the combinationsaccording to the invention rapidly and/or in a modified manner and whichcontain the compounds, which are constituents of the combination, incrystalline and/or amorphized and/or dissolved form, for example tablets(non-coated or coated tablets, for example with gastric juice-resistantor retarded-dissolution or insoluble coatings which control the releaseof the compounds on which the combinations according to the inventionare based), tablets or films/wafers which disintegrate rapidly in theoral cavity, films/lyophilizates, capsules (for example hard or softgelatin capsules), sugar-coated tablets, granules, pellets, powders,emulsions, suspensions, aerosols or solutions.

Preferred administration forms include tablet forms (non-coated orcoated tablets, for example with gastric juice-resistant orretarded-dissolution or insoluble coatings, which control the release ofthe compounds on which the combinations according to the invention arebased), tablets or films/wafers which disintegrate rapidly in the oralcavity and particularly preferred administration forms are tablet forms(non-coated or coated tablets, for example with gastric juice-resistantor retarded-dissolution or insoluble coatings, which control the releaseof the components on which the combinations according to the inventionare based), tablets or films/wafers which disintegrate rapidly in theoral cavity.

Parenteral administration can be accomplished with avoidance of aresorption step (for example by an intravenous, intraarterial,intracardiac, intraspinal or intralumbar route) or with inclusion of aresorption (for example by an intramuscular, subcutaneous,intracutaneous, percutaneous or intraperitoneal route). Administrationforms suitable for parenteral administration include inter aliapreparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalationmedicaments (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets for lingual, sublingual or buccaladministration, films/wafers or capsules, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, dustingpowders, implants or stents.

Preference is given to oral or parenteral administration, oraladministration being more preferred. Particular preference is given tooral administration by means of tablet form.

In the combinations according to the invention, the components can beconverted into the administration forms mentioned. This can beaccomplished in a manner known per se by mixing with inert, non-toxic,pharmaceutically suitable excipients. These excipients include interalia carriers (for example microcrystalline cellulose, lactose,mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers anddispersing or wetting agents (for example sodium dodecylsulfate,polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone),synthetic and natural polymers (for example albumin), stabilizers (e.g.antioxidants, for example ascorbic acid), colourants (e.g. inorganicpigments, for example iron oxides) and flavor and/or odour correctors.

In the combinations according to the invention, the components may beadministered together or successively or separately in a combined unitdosage form, in two separate unit dosage forms, or in three separateunit dosage forms. The unit dosage form may also be a fixed combination.

A therapeutically effective amount of each component of the combinationaccording to the invention may be administered simultaneously orsequentially in any sequence.

In one embodiment, the components may be present in a so-calleddelayed-release formulation in which the release of the componentsaccording to the invention takes place at different times. By way ofexample, mention may be made of a tablet with delayed-releasedissolution coatings, each of which contains one or more components ofthe combinations according to the invention.

In one embodiment of the invention, in the case of oral administration,the dose of the sGC stimulator and/or sGC activator is around 1.25-20mg, 1.25-5 mg od, around 5-10 mg od or 10 to 20 mg od.

In one embodiment of the invention, the dose of valsartan is around20-110 mg bid, 20-50 mg bid or 50-110 mg bid.

In one embodiment of the invention, the dose of the NEP inhibitor isaround 20-100 mg bid, around 20-50 mg bid or 50 to 100 mg bid.

In one embodiment of the invention, the dose of LCZ696 is around 40-400mg, 50-200 mg bid, 50-100 mg bid or 100-200 mg bid.

In one embodiment of the invention, valsartan is provided in the form ofa suitable unit dosage form, a capsule or tablet for example, andcontains a therapeutically effective amount of, for example, 20 to 320mg of valsartan, which can be administered to patients. The activeingredient may be administered three times a day, starting from a dailydose of 20 mg or 40 mg of valsartan for example, which increases over 80mg daily and further to 160 mg daily to 320 mg daily. Preferably,valsartan is administered once a day or twice a day to patients withheart failure at a dose of 80 mg or 160 mg respectively. Correspondingdoses can be taken, for example, in the morning, at noon or at night. Inthe case of heart failure, preference is given to q.d. or b.i.d.administration.

In one embodiment of the invention, the NEP inhibitor is administered inunit forms, tablets or capsules for example, which contain for example20 mg to 800 mg, preferably 50 mg to 700 mg, more preferably 100 mg to600 mg and even more preferably 100 mg to 300 mg, which are administeredonce a day.

The doses described above may be formulated in the context of theinvention as a fixed dose combination in which the preferred unit formsmay be tablets or capsules.

In a preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 2.5-20 mg od, the dose ofvalsartan is about 25 mg bid and the dose of the NEP inhibitor is about25 mg bid, also preferably the dose of the sGC stimulator and/or sGCactivator is about 2.5-20 mg od, the dose of valsartan is about 50 mgbid and the dose of the NEP inhibitor is about 50 mg bid and alsopreferably the dose of the sGC stimulator and/or sGC activator is about2.5-20 mg od, the dose of valsartan is about 100 mg bid and the dose ofthe NEP inhibitor is about 100 mg bid.

In a preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 5-10 mg od, the dose ofvalsartan is about 25 mg bid and the dose of the NEP inhibitor is about25 mg bid, also preferably the dose of the sGC stimulator and/or sGCactivator is about 5-10 mg od, the dose of valsartan is about 50 mg bidand the dose of the NEP inhibitor is about 50 mg bid and also preferablythe dose of the sGC stimulator and/or sGC activator is about 5-10 mg od,the dose of valsartan is about 100 mg bid and the dose of the NEPinhibitor is about 100 mg bid.

In a preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 2.5-5 mg od, the dose ofvalsartan is about 25 mg bid and the dose of the NEP inhibitor is about25 mg bid, also preferably the dose of the sGC stimulator and/or sGCactivator is about 2.5-5 mg od, the dose of valsartan is about 50 mg bidand the dose of the NEP inhibitor is about 50 mg bid and also preferablythe dose of the sGC stimulator and/or sGC activator is about 2.5-5 mgod, the dose of valsartan is about 100 mg bid and the dose of the NEPinhibitor is about 100 mg bid.

In a preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 10-20 mg od, the dose ofvalsartan is about 25 mg bid and the dose of the NEP inhibitor is about25 mg bid, also preferably the dose of the sGC stimulator and/or sGCactivator is about 10-20 mg od, the dose of valsartan is about 50 mg bidand the dose of the NEP inhibitor is about 50 mg bid and also preferablythe dose of the sGC stimulator and/or sGC activator is about 10-20 mgod, the dose of valsartan is about 100 mg bid and the dose of the NEPinhibitor is about 100 mg bid.

In a further preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 2.5-20 mg od and the dose ofLCZ696 is about 50 mg bid, also preferably the dose of the sGCstimulator and/or sGC activator is about 5-10 mg od and the of LCZ696 isabout 100 mg bid and also preferably the dose of the sGC stimulator orsGC activator is about 2.5-5 mg od and the dose of LCZ696 is about 200mg bid.

In a further preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 10-20 mg od and the dose ofLCZ696 is about 50 mg bid, also preferably the dose of the sGCstimulator and/or sGC activator is about 10-20 mg od and the of LCZ696is about 100 mg bid and also preferably the dose of the sGC stimulatorand/or sGC activator is about 10-20 mg od and the dose of LCZ696 isabout 200 mg bid.

In a further preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 2.5-5 mg od and the dose ofLCZ696 is about 50 mg bid, also preferably the dose of the sGCstimulator and/or sGC activator is about 2.5-5 mg od and the of LCZ696is about 100 mg bid and also preferably the dose of the sGC stimulatorand/or sGC activator is about 2.5-5 mg od and the dose of LCZ696 isabout 200 mg bid.

In a further preferred embodiment of the invention, the dose of the sGCstimulator and/or sGC activator is about 5-10 mg od and the dose ofLCZ696 is about 50 mg bid, also preferably the dose of the sGCstimulator and/or sGC activator is about 5-10 mg od and the of LCZ696 isabout 100 mg bid and also preferably the dose of the sGC stimulatorand/or sGC activator is about 5-10 mg od and the dose of LCZ696 is about200 mg bid.

It may nevertheless be necessary in some cases to deviate from thestated amounts, and specifically as a function of body weight, route ofadministration, individual response to the active ingredient, nature ofthe preparation and time or interval over which administration takesplace. Thus in some cases it may be sufficient to manage with less thanthe abovementioned minimum amount, while in other cases the upper limitmentioned must be exceeded. In the case of administration of greateramounts, it may be advisable to divide them into several individualdoses over the day.

EXPERIMENTAL SECTION

The working examples which follow illustrate the invention. Theinvention is not restricted to the examples.

Unless stated otherwise, the percentages in the tests and examples whichfollow are percentages by weight; parts are parts by weight. Solventratios, dilution ratios and concentration data for liquid/liquidsolutions are based in each case on volume.

Assessment of Physiological Efficacy

The suitability of the combinations according to the invention fortreating cardiovascular disorders can be demonstrated in the followingassay systems:

Radiotelemetric Measurement of Blood Pressure and Heart Rate ofConscious Rats

A commercially available telemetry system from Data SciencesInternational DSI, USA, was employed for the measurements on consciousrats (Wistar strain Unilever/WU or Spontaneous Hypertensive Rat/SHR)described below. The system consists of 3 main components: (1)implantable transmitters (PhysioTel® telemetry transmitter), (2)receivers (PhysioTel® receiver), which are linked via a multiplexer (DSIData Exchange Matrix) to a (3) data acquisition computer. The telemetrysystem makes it possible to continuously record blood pressure, heartrate and body motion of conscious animals in their usual habitat.

The studies are conducted on adult female rats with a body weightof >200 g. After transmitter implantation, the experimental animals arehoused singly in type III Makrolon® cages. They have free access tostandard feed and water. The day/night rhythm in the test laboratory isset by changing the illumination of the room.

Transmitter Implantation

The telemetry transmitters used (e.g. PA-C40 HD-S10, DSI) are surgicallyimplanted under aseptic conditions in the experimental animals at least14 days before the first experimental use.

For the implantation, the fasted animals are anesthetized withisoflurane (IsoFlo®, Abbott, initiation 5%, maintenance 2%) and shavedand disinfected over a large area of their abdomens. After the abdominalcavity has been opened along the linea alba, the liquid-filled measuringcatheter of the system is inserted into the descending aorta in thecranial direction above the bifurcation and fixed with tissue glue(Vetbond™, 3M). The transmitter housing is fixed intraperitoneally tothe abdominal wall muscle, and the wound is closed layer by layer.Post-operatively, an antibiotic (Ursocyclin® 10%, 60 mg/kg s.c., 0.06ml/100 g body weight, Serumwerk Bernburg AG, Germany) for infectionprophylaxis and an analgesic (Rimadyl®, 4 mg/kg s.c., Pfizer, Germany)are administered.

Substances and Solutions

Unless stated otherwise, the substances to be studied are administeredorally to a group of animals in each case (n=6). In accordance with anadministration volume of 2 ml/kg of body weight, the test substances aredissolved in suitable solvent mixtures. A solvent-treated group ofanimals is used as control.

Experimental Outline

The telemetry measuring system is configured for 24 animals.

Each of the instrumented rats living in the system is assigned aseparate receiving antenna (RPC-1 Receiver, DSI). The implanted senderscan be activated externally via an installed magnetic switch and areswitched to transmission during the pre-run of the experiment. Thesignals emitted can be detected online by a data acquisition system(Dataquest™ A.R.T. for Windows, DSI or Ponemah, DSI) and processedaccordingly.

In the standard procedure, the following are measured for 10-secondperiods in each case: (1) systolic blood pressure (SBP), (2) diastolicblood pressure (DBP), (3) mean arterial pressure (MAP), (4) heart rate(HR) and (5) activity (ACT). These parameters are measured over 24 hoursafter administration.

The acquisition of measurements is repeated under computer control at5-minute intervals. The source data obtained as absolute values arecorrected in the diagram with the currently measured barometric pressure(Ambient Pressure Reference Monitor, APR-1, DSI).

Evaluation

After the end of the experiment, the acquired individual data are sortedusing the analysis software (Dataquest™ A.R.T. 4.1 Analysis or Ponemah,DSI). The 2 hour time point before substance administration is assumedas the blank value.

The data are smoothed over a presettable period by determination of themeans (30 minute mean).

Literature

K. Witte, K. Hu, J. Swiatek, C. MUssig, G. Ertl and B. Lemmer,Experimental heart failure in rats: effects on cardiovascular circadianrhythms and on myocardial (3-adrenergic signaling, Cardiovasc. Res. 47(2): 203-405, 2000.

Long-Term Study in Ren-2 Transgenic Rats Treated With L-NAME

The cardiovascular effect after administration of an sGC modulator,neprilysin inhibitor, angiotensin AII antagonist and double and triplecombinations thereof are demonstrated by determining the long-termeffects on hemodynamic and hormonal parameters in a high renin, low-NOblood pressure model in rats.

Male transgenic Ren-2 rats (TGR(mRen2)27) are raised on-site and keptunder controlled light and temperature conditions. From an age of 10 to20 weeks the animals are randomized into different groups. The controlgroup receive a placebo, the test groups sGC modulators, neprilysininhibitors, angiotensin AII antagonists and double and triplecombinations thereof for 4-10 weeks. The rats of the placebo andtreatment groups also receive 30-100 mg/l L-NAME via drinking water. Thetest substances are administered p.o. as a suspension in a mixture oftranscutol/cremophor/water (10/20/70=v/v/v) or as a tylose suspension.Systolic blood pressure and heart rate are measured weekly using the“tail-cuff” method in conscious animals in cages at a constanttemperature of 37° C. Urine collections occur on day 0, during and atthe end of the experiment in metabolism cages and proteinuria, urinaryelectrolyte excretion are determined. At the end of the studies, leftventricular pressure and cardiac contraction are measured underanesthesia. Finally, the animals are sacrificed by decapitation andblood samples withdrawn. Plasma and urine parameters are biochemicallydetermined, e.g. ANP (RIA Kit RK 005-24, Phoenix Pharmaceuticals, Inc.,USA), cGMP (RIA Kit RE29075, IBL International GmbH, Germany), renin,angiotensin I (RIA Kit CA-1533, DiaSorin S.p.A., Italy) and aldosterone(P2714, DiaSorin S.p.A., Italy). Organs, e.g. kidney, heart, lungs etc.are taken and gene expression profiles and histopathological data arecollected.

Hypertensive Heart Failure Model in Dogs

The cardiovascular effect after administration of an sGC modulator (sGCstimulator or sGC activator), neprilysin inhibitor, angiotensin AIIantagonist, and double and triple combinations thereof are evaluated ina dog model of “mild” systolic heart failure caused by angiotensin AIIantagonist-induced acute hypertension. An experimental animal model ofleft ventricular dysfunction is triggered by right ventricular“tachypacing” at 180 bpm for 10 days. The experimental implementation ofthis model has been described in detail. [Redfield et al., Circulation1993;87:2016-2022]

Hypertensive “Renal Wrap” Dogs

The effect of an sGC modulator (sGC stimulator or sGC activator),neprilysin inhibitor, angiotensin AII antagonist, and double and triplecombinations thereof on blood pressure and heart rate are tested in thehypertensive “renal wrap” dog model. In the model a kidney is wrappedwith silk, while the second kidney is subjected to an occlusion of themain kidney artery. [Page et al., Science 1939; 89: 2307-2308; Goldblattet al., Proc Natl Acad Sci 1976; 73: 1722-1724]. About 4 weeks after theoperation, the dogs develop stable high blood pressure.

Results

Results are shown in FIGS. 1 and 2 for the compound of the formula (6)in a triple combination with a neprilysin inhibitor and an angiotensinAII antagonist compared to the single administration of the compound ofthe formula (6) and a double combination of a neprilysin inhibitor andan angiotensin AII antagonist.

The compound of the formula (6) shows no hemodynamic effects (bloodpressure, heart rate) at an oral dose of 0.1 mg/kg; at 0.3 mg/kg adecrease in the mean arterial blood pressure of ca. −10% and a transientincrease in heart rate was observed. The comparative substances, whichare administered orally as a double combination, show a decrease in themean arterial blood pressure of ca. −20% with associated reflextachycardia at the dose investigated. The addition of 0.1 mg/kg of thecompound of the formula (6) to the double combination leads, comparedwith the double combination alone, to a reduced reflexive increase inthe heart rate with the same decrease in the mean arterial bloodpressure. The combination of the compound of the formula (6) at a doseof 0.3 mg/kg with a neprilysin inhibitor and an angiotensin AIIantagonist shows an additional effect on the blood pressure decrease.Surprisingly, a non-additive effect on the heart rate was observed inthe triple-combination trial (no additive compensatory effect or reflextachycardia). In the double and triple combination, 30 mg/kg sacubitriland 10 mg/kg valsartan is used.

Results are shown in FIGS. 3, 4 and 5 for the compound of the formula(29) in a triple combination with a neprilysin inhibitor and anangiotensin AII antagonist compared to the single administration of thecompound of the formula (29) and a double combination of a neprilysininhibitor and an angiotensin AII antagonist.

The compound of the formula (29) shows a decrease in the mean arterialblood pressure of ca. −10% or 15% and an associated reflex tachycardiaat an oral dose of 3 mg/kg and 10 mg/kg. The compound of the formula(29) shows reflex tachycardia at an oral dose of 1 mg/kg. Thecomparative substances, which are administered orally as a doublecombination, show a decrease in the mean arterial blood pressure of ca.−15% at the dose investigated. The triple combination of the compound ofthe formula (29) with a neprilysin inhibitor and an angiotensin AIIantagonist shows an effect on the blood pressure decrease. In the doubleand triple combination, 30 mg/kg sacubitril and 10 mg/kg valsartan isused.

Description of the Figures

FIG. 1: B-x) mean arterial blood pressure and heart rate as % deviationversus time [h] after substance administration; compound of the formula(6), 0.3 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10mg/kg valsartan p.o., triple combination: compound of the formula (6),0.3 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

FIG. 2: B-x) mean arterial blood pressure and heart rate as % deviationversus time [h] after substance administration; compound of the formula(6), 0.1 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10mg/kg valsartan p.o., triple combination: compound of the formula (6),0.1 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

FIG. 3: B-x) mean arterial blood pressure and heart rate as % deviationversus time [h] after substance administration; compound of the formula(29), 10 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10mg/kg valsartan p.o., triple combination: compound of the formula (29),10 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

FIG. 4: B-x) mean arterial blood pressure and heart rate as % deviationversus time [h] after substance administration; compound of the formula(29), 3 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10 mg/kgvalsartan p.o., triple combination: compound of the formula (29), 3mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

FIG. 5: B-x) mean arterial blood pressure and heart rate as % deviationversus time [h] after substance administration; compound of the formula(29), 1 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10 mg/kgvalsartan p.o., triple combination: compound of the formula (29), 1mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

1. A combination comprising an sGC stimulator, sacubitril and/or anangiotensin AII antagonist and also in each case the salts, solvates andsolvates of the salts thereof
 2. The combination as claimed in claim 1comprising an sGC stimulator, sacubitril and/or valsartan and also ineach case the salts, solvates and solvates of the salts thereof
 3. Thecombination as claimed in claim 1 comprising an sGC stimulator andLCZ696 and also in each case the salts, solvates and solvates of thesalts thereof.
 4. The combination as claimed in claim 1 for preparing amedicament for the treatment and/or prophylaxis of cardiovasculardisorders, renal disorders, lung disorders, and also for the treatmentand/or prophylaxis of fibrotic disorders.
 5. A medicament comprising acombination as claimed in claim 1 in combination with an inert,non-toxic, pharmaceutically suitable excipient.
 6. The medicamentcomprising a combination as claimed in claim 1 in combination with oneor more further active ingredients selected from the group consisting ofACE inhibitors, renin inhibitors, beta blockers, acetylsalicylic acid,diuretics, calcium antagonists, statins, digitalis (digoxin)derivatives, calcium sensitizers, nitrates and antithrombotics.
 7. Themedicament comprising a combination as claimed in claim 1 for thetreatment and/or prophylaxis of cardiovascular disorders, renaldisorders, lung disorders, and also for the treatment and/or prophylaxisof fibrotic disorders.
 8. A method for the treatment and/or prophylaxisof cardiovascular disorders, renal disorders, lung disorders, and alsofor the treatment and/or prophylaxis of fibrotic disorders, in humansand animals comprising administering a therapeutically effective amountof the combination of claim 1 to a human or animal in need thereof.
 9. Akit comprising a pharmaceutical composition comprising an sGC stimulatorand a pharmaceutical composition comprising an angiotensin AIIantagonist and N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid or the esters thereof.
 10. Thekit as claimed in claim 9 comprising a pharmaceutical compositioncomprising an sGC stimulator and a pharmaceutical composition comprisingvalsartan andN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid or an ester thereof.
 11. The kit as claimed in claim 9 comprising apharmaceutical composition comprising an sGC stimulator and apharmaceutical composition comprising trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate]hemipentahydrate.